rs2715554

Variant names:

• chr17-40332918-A-G
• rs2715554
• NM_000964.4:c.178+1522A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000964.4(RARA):​c.178+1522A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0986 in 152,286 control chromosomes in the GnomAD database, including 1,026 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.099 (1026 hom., cov: 33)
• Consequence: RARA NM_000964.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.844
• Publications: 28 publications found

Genes affected

RARA (HGNC:9864): (retinoic acid receptor alpha) This gene represents a nuclear retinoic acid receptor. The encoded protein, retinoic acid receptor alpha, regulates transcription in a ligand-dependent manner. This gene has been implicated in regulation of development, differentiation, apoptosis, granulopoeisis, and transcription of clock genes. Translocations between this locus and several other loci have been associated with acute promyelocytic leukemia. Alternatively spliced transcript variants have been found for this locus.[provided by RefSeq, Sep 2010]

RARA Gene-Disease associations (from GenCC):

• multiple congenital anomalies/dysmorphic syndrome

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• acute promyelocytic leukemia

  Inheritance: AD Classification: NO_KNOWN Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.147 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RARA	NM_000964.4	c.178+1522A>G		intron_variant	Intron 2 of 8	ENST00000254066.10	NP_000955.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RARA	ENST00000254066.10	c.178+1522A>G		intron_variant	Intron 2 of 8	1	NM_000964.4	ENSP00000254066.5
RARA	ENST00000425707.7	c.178+1522A>G		intron_variant	Intron 2 of 6	1		ENSP00000389993.3
RARA	ENST00000394089.6	c.178+1522A>G		intron_variant	Intron 2 of 8	2		ENSP00000377649.2
RARA	ENST00000577646.5	c.178+1522A>G		intron_variant	Intron 3 of 3	5		ENSP00000464287.1

Frequencies

GnomAD3 genomes AF: 0.0988 AC: 15028 AN: 152168 Hom.: 1026 Cov.: 33

Gnomad AFR AF: 0.0296

Gnomad AMI AF: 0.0439

Gnomad AMR AF: 0.0684

Gnomad ASJ AF: 0.161

Gnomad EAS AF: 0.00116

Gnomad SAS AF: 0.0656

Gnomad FIN AF: 0.137

Gnomad MID AF: 0.101

Gnomad NFE AF: 0.149

Gnomad OTH AF: 0.102

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0986 AC: 15020 AN: 152286 Hom.: 1026 Cov.: 33 AF XY: 0.0949 AC XY: 7068 AN XY: 74462

African (AFR) AF: 0.0295 AC: 1225 AN: 41568

American (AMR) AF: 0.0683 AC: 1045 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.161 AC: 560 AN: 3472

East Asian (EAS) AF: 0.00116 AC: 6 AN: 5178

South Asian (SAS) AF: 0.0654 AC: 316 AN: 4830

European-Finnish (FIN) AF: 0.137 AC: 1450 AN: 10608

Middle Eastern (MID) AF: 0.0918 AC: 27 AN: 294

European-Non Finnish (NFE) AF: 0.149 AC: 10138 AN: 68004

Other (OTH) AF: 0.101 AC: 213 AN: 2112

Alfa AF: 0.123 Hom.: 3321

Bravo AF: 0.0910

Asia WGS AF: 0.0360 AC: 123 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.38
DANN	Benign	0.49
PhyloP100		-0.84
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2715554; hg19: chr17-38489170;